Therapeutic Effects of Environmental Enrichment on Cognitive Function and Tissue Integrity Following Severe Traumatic Brain Injury in Rats

Postinjury environmental enrichment (EE) has been shown to alter functional and anatomical outcomes in a number of injury paradigms, including traumatic brain injury (TBI). The question of whether EE alters functional outcome following TBI in a model which produces overt histopathological consequences has not been addressed. We investigated this question using the severe, parasagittal fluid percussion injury (FPI) model. Rats (n = 7 per group, enriched and standard for behavior; n = 15 per group for histology) underwent severe (2.2-2.6 atm) FPI, with sham-operated rats (n = 7 per group, enriched and standard for behavior; n = 6 enriched, n = 3 standard for histology) serving as controls. Animals were allowed to recover for 11 days either in standard single housing or together (injured and sham) in an enriched environment consisting of a 92 x 61 x 77-cm ferret cage filled with various stimulatory objects. Consistent with earlier reports, injured animals recovering in the enriched environment showed significantly (P < 0.05) shorter latencies to find the platform in a Morris Water Maze task versus injured/standard animals on day 12 post-TBI. However, both injured groups showed significant deficits versus sham groups (P < 0.05). There were no differences between the sham/enriched and sham/standard groups. No significant group differences in swim speed were observed. At 14 days post-TBI, enriched animals had approximately twofold smaller lesion areas in regions of the cerebral cortex posterior to the injury epicenter (-4.5, -5.8, -6.8 mm relative to bregma; P < 0.05) compared to injured/standard animals. In addition, overall lesion volume for the entire injured cortical hemisphere was significantly smaller in animals recovering in the enriched environment. These results indicate that noninvasive environmental stimulation is beneficial in attenuating cognitive deficits and preserving tissue integrity in a TBI model which causes cerebral contusion and cell death.

[1]  E. J. Green,et al.  Hippocampally dependent and independent chronic spatial navigational deficits following parasagittal fluid percussion brain injury in the rat , 1997, Brain Research.

[2]  E. J. Green,et al.  Temporal and Regional Patterns of Axonal Damage following Traumatic Brain Injury: A Beta‐amyloid Precursor Protein Immunocytochemical Study in Rats , 1997, Journal of neuropathology and experimental neurology.

[3]  Joseph W. Harding,et al.  Effects of discrete kainic acid-induced hippocampal lesions on spatial and contextual learning and memory in rats , 1996, Brain Research.

[4]  B. Winblad,et al.  Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment , 1992, Neuroscience Letters.

[5]  J. Liepert,et al.  Treatment-induced cortical reorganization after stroke in humans. , 2000, Stroke.

[6]  P. Kochanek,et al.  One-year study of spatial memory performance, brain morphology, and cholinergic markers after moderate controlled cortical impact in rats. , 1999, Journal of neurotrauma.

[7]  A. Risedal,et al.  Early Training May Exacerbate Brain Damage after Focal Brain Ischemia in the Rat , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  B. Winblad,et al.  Environmental influence on behaviour and nerve growth factor in the brain , 1990, Brain Research.

[9]  H. Levin,et al.  Cognitive function outcomes after traumatic brain injury. , 1998, Current opinion in neurology.

[10]  T. Schallert,et al.  Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period , 1998, Brain Research.

[11]  J. Trojanowski,et al.  Enduring cognitive, neurobehavioral and histopathological changes persist for up to one year following severe experimental brain injury in rats , 1998, Neuroscience.

[12]  D. Lowenstein,et al.  Persistent memory dysfunction is associated with bilateral hippocampal damage following experimental brain injury , 1994, Neuroscience Letters.

[13]  T. Schallert,et al.  Use-Dependent Exaggeration of Neuronal Injury after Unilateral Sensorimotor Cortex Lesions , 1996, The Journal of Neuroscience.

[14]  A. Marmarou,et al.  A fluid percussion model of experimental brain injury in the rat. , 1987, Journal of neurosurgery.

[15]  R. Morris,et al.  Place navigation impaired in rats with hippocampal lesions , 1982, Nature.

[16]  J. Grotta,et al.  Early exclusive use of the affected forelimb after moderate transient focal ischemia in rats : functional and anatomic outcome. , 2000, Stroke.

[17]  H. Levin,et al.  Facilitation of memory performance through induced semantic processing in survivors of severe closed-head injury. , 1990, Journal of clinical and experimental neuropsychology.

[18]  G. Clifton,et al.  Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat , 1990, Brain Research.

[19]  H. Levin,et al.  Cognitive impairment following closed head injury. , 1992, Neurologic clinics.

[20]  T. Yamaki,et al.  Evaluation of learning and memory dysfunction and histological findings in rats with chronic stage contusion and diffuse axonal injury , 1997, Brain Research.

[21]  L. Jarrard,et al.  Fimbria–Fornix vs Selective Hippocampal Lesions in Rats: Effects on Locomotor Activity and Spatial Learning and Memory , 1998, Neurobiology of Learning and Memory.

[22]  B. Mattsson,et al.  Environmental influence on gene expression and recovery from cerebral ischemia. , 1999, Acta neurochirurgica. Supplement.

[23]  B. Johansson Functional outcome in rats transferred to an enriched environment 15 days after focal brain ischemia. , 1996, Stroke.

[24]  I. Whishaw,et al.  Decortication abolishes place but not cue learning in rats , 1984, Behavioural Brain Research.

[25]  R. Morris Developments of a water-maze procedure for studying spatial learning in the rat , 1984, Journal of Neuroscience Methods.

[26]  M. Thomas,et al.  Evaluation of memory dysfunction following experimental brain injury using the Morris water maze. , 1991, Journal of neurotrauma.

[27]  B. Winblad,et al.  Expression of neurotrophin-3 mRNA in the rat visual cortex and hippocampus is influenced by environmental conditions , 1996, Neuroscience Letters.

[28]  Karl J. Zilles,et al.  The Cortex of the Rat: A Stereotaxic Atlas , 1985 .

[29]  Tilson Ha,et al.  Behavioral impairment in the rat after colchicine lesions of the hippocampus and nucleus basalis. , 1988 .

[30]  B. Pike,et al.  Exposure to environmental complexity promotes recovery of cognitive function after traumatic brain injury. , 1996, Journal of neurotrauma.

[31]  R. Grossman,et al.  Long-term neuropsychological outcome of closed head injury. , 1979, Journal of neurosurgery.

[32]  F. Gage,et al.  Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus , 1999, Nature Neuroscience.

[33]  B. Pike,et al.  Working memory deficits following traumatic brain injury in the rat. , 1996, Journal of neurotrauma.

[34]  W. Stummer,et al.  Reduced Mortality and Brain Damage After Locomotor Activity in Gerbil Forebrain Ischemia , 1994, Stroke.

[35]  B. Pike,et al.  Selective cognitive impairment following traumatic brain injury in rats , 1993, Behavioural Brain Research.

[36]  John P Aggleton,et al.  Differential deficits in the Morris water maze following cytotoxic lesions of the anterior thalamus and fornix transection , 1998, Behavioural Brain Research.

[37]  H. Levin,et al.  Disproportionately severe memory deficit in relation to normal intellectual functioning after closed head injury. , 1988, Journal of neurology, neurosurgery, and psychiatry.

[38]  T. Schallert,et al.  Use-dependent structural events in recovery of function. , 1997, Advances in neurology.

[39]  L. Nadel,et al.  Lateralized fascia dentata lesion and blockade of one hippocampus: Effect on spatial memory in rats , 1998, Hippocampus.

[40]  R. C. Honey,et al.  Dissociable effects of selective lesions to hippocampal subsystems on exploratory behavior, contextual learning, and spatial learning. , 1997, Behavioral neuroscience.

[41]  R. Chesnut,et al.  Effect of cognitive rehabilitation on outcomes for persons with traumatic brain injury: A systematic review. , 1999, The Journal of head trauma rehabilitation.

[42]  F. Gonzalez-Lima,et al.  Metabolic activation of the brain of young rats after exposure to environmental complexity. , 1994, Developmental psychobiology.

[43]  M. Oddy,et al.  Social recovery during the year following severe head injury. , 1980, Journal of neurology, neurosurgery, and psychiatry.

[44]  R. P. Stroemer,et al.  Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. , 1998, Stroke.

[45]  D. Lowenstein,et al.  Mild experimental brain injury in the rat induces cognitive deficits associated with regional neuronal loss in the hippocampus. , 1993, Journal of neurotrauma.

[46]  J Q Trojanowski,et al.  Progressive atrophy and neuron death for one year following brain trauma in the rat. , 1997, Journal of neurotrauma.

[47]  M. Dragunow,et al.  Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective , 1999, Nature Medicine.

[48]  R. Busto,et al.  Posttraumatic cerebral ischemia after fluid percussion brain injury: an autoradiographic and histopathological study in rats. , 1998, Neurosurgery.

[49]  B. Winblad,et al.  Environmental enrichment results in higher levels of nerve growth factor mRNA in the rat visual cortex and hippocampus , 1998, Behavioural Brain Research.

[50]  J. W. Rudy,et al.  Brief exposure to an enriched environment improves performance on the Morris water task and increases hippocampal cytosolic protein kinase C activity in young rats , 1992, Behavioural Brain Research.

[51]  E. J. Green,et al.  Chronic histopathological consequences of fluid-percussion brain injury in rats: effects of post-traumatic hypothermia , 1997, Acta Neuropathologica.

[52]  T. Langfitt,et al.  Influence of lesions detected by computed tomography on outcome and neuropsychological recovery after severe head injury. , 1987, Neurosurgery.

[53]  R. Raghupathi,et al.  Metabolic quantification of lesion volume following experimental traumatic brain injury in the rat. , 1997, Journal of neurotrauma.

[54]  T. Coughlan,et al.  Social adjustment after closed head injury: a further follow-up seven years after injury. , 1985, Journal of neurology, neurosurgery, and psychiatry.

[55]  A. Wyler,et al.  Memory and head injury severity. , 1987, Journal of neurology, neurosurgery, and psychiatry.

[56]  M. Oddy,et al.  Subjective impairment and social recovery after closed head injury. , 1978, Journal of neurology, neurosurgery, and psychiatry.

[57]  F. Gage,et al.  More hippocampal neurons in adult mice living in an enriched environment , 1997, Nature.